Invasive pulmonary aspergillosis (IPA) is a rapidly progressive and oftentimes fatal disease common among severely immunocompromised individuals, including patients with hematologic malignancies, neutropenia, chronic granulomatous disease, solid organ transplants (SOT), allogeneic hematopoietic cell transplants (HCT), AIDS, or major burns. Despite the development and use of new antifungal agents and the implementation of antifungal prophylaxis, the incidence and mortality rates remain high (Lin 2001).
IPA is most frequently observed in SOT and HCT recipients following the prolonged immunosuppression required to avoid graft rejection (Duthie 1995; Denning 1998; Maschke 1999; Ho 2000; Baddley 2001; Subira 2002; Kibbler 2003; Wiederhold 2003). The ubiquitous mold Aspergillus fumigatus is the most frequently isolated causative agent of IPA (Latge 1999a). A. fumigatus is also involved in allergic bronchopulmonary aspergillosis (ABPA) and other fungal diseases.
Healthy individuals rarely contract respiratory fungal infections, being protected against inhaled spores (conidia) through innate immunity provided by alveolar macrophages and neutrophils (Schaffner 1982). Opsonizing antibodies have been suggested to play a role in enhancing phagocytosis of conidia and in B-cell mediated memory immunity (Montagnoli 2003). The immunosuppressive effects of corticosteroids are thought to be due to suppression of the antimicrobial activity of macrophages and neutrophils (Schaffner 1985; Roilides 1993a). Although cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-γ) prevent corticosteroid-induced immunosuppression in vitro (Roilides 1993a; Roilides 1993b), use of these cytokines has not been shown to restore immunocompetence or to prevent or enhance therapy of invasive aspergillosis (Casadevall 2001).
Currently available antifungal agents have had only limited success in treating IPA (Ho 2000) and are also associated with serious toxicities such as nephrotoxicity and hepatotoxicity (Ho 2000; Gupta 2003; Hamza 2004). Therefore, there is a need for new antifungal agents that prevent and treat IPA and other diseases caused by Aspergillus with minimal toxicity.